Non-replicating viruses and viral vectors were originally proposed 20 years ago as anticancer agents using modalities that are ablative (e.g. prodrug activation such as thymidine kinase plus gancyclovir), restorative of normal cellular function (e.g., p53), immune activating (e.g., IL-2) or some combination of these (see, for example, Crofts and Krimsky Hum Gene Ther. 16:169-177, 2005). However, it has become apparent that non-replicative vectors are very inefficient in delivering genes to whole animals or patients as injection into tissues does not allow transduction past areas close to the needle track (see, e.g., Lang et al., J Clin Oncol 21:2508-2518, 2003) and injection into the vasculature or other body fluids makes the individual particles very susceptible to various arms of the immune system such as complement and pre-existing adaptive immunity (see, e.g., Liu et al., Hum Gene Ther. 20:621-629, 2009).
Therefore in the past few years there has been a revival of interest in the use of replicative viruses and replicative viral vectors as disease fighting agents in general, and anti-cancer agents in particular. With the advent of chemotherapy, radiation treatment and modern surgical techniques, enthusiasm for this approach lagged and for several decades these three approaches, along with the more recent addition of active immunotherapy with monoclonal antibodies, have been the major modes of treatment. However, the limitations of these four approaches on overall cancer mortality have become more and more apparent, and led first to the attempts at therapy with non-replicative viral vectors, and more recently, replicative vectors with and without additional genes. The hope has been that the viruses would replicate through tumors and destroy them directly or by expression of a transgene. Currently replicative viruses or viral vectors based on adenovirus, herpes virus, vesicular stomatitis virus, reovirus, vaccinia virus, measles virus, alpha virus and others are being investigated (Stanford et al., Cytokine Growth Factor Rev., 21:177-83, 2010).
However, even after the advances over the last half century in the understanding of viruses and their interaction with their target cells, this effort has been largely frustrated by some of the same factors as before. In particular it has become apparent that most viruses that infect and lyse target cells as they replicate tend to engender rapid adaptive and inflammatory immune responses that lead to: rapid clearance of the hopefully therapeutic agent; continued tumor growth; and an inability to effectively re-administer (Choicca, Curr. Opin. Mol. Ther., 10:38-45, 2008). In addition there is often infection of non-diseased tissue. In reaction to these issues attempts have been made to selectively attenuate the viruses, use non-virulent strains (such as vaccine strains) and implant some tissue specificity in the viruses, such as by putting genes with key replicative functions in the virus under the control of tissue specific promoters or responsive to the tumor environment. Such attempts have had, at best, limited success in large part because of limited understanding of the host viral interactions.